Over the past century, groundbreaking discoveries in the field of antibiotics have resulted in the saving of countless lives. This can be primarily attributed to their broad-spectrum activity that is ideal for the treatment of a wide range of bacterial infections but can also result in significant misuse and unintended side effects Cox et al., 2014, Cell 158:705). For example, recent work from the Blaser lab strongly suggests that prolonged broad-spectrum antibiotic exposure early in life can lead to an increased likelihood of obesity, allergies, and inflammatory diseases (Cox et al., 2014, Cell 158:705). These findings highlight the effect that certain antimicrobials have on one's commensal population, resulting in an altered community dynamic and leading to undesired outcomes lending credence to the recent call for the development of narrow-spectrum therapies.
To date very few options currently exist for pathogen-specific treatments (Maxson and Mitchell, 2016, Tetrahedron). Furthermore, with species-specific compounds in hand one would also have access to tool compounds to aid in deconvoluting the complex multispecies environments present. The recent advances in genetic sequencing, as exemplified by the human microbiome project, would allow for the probing of these environments if the appropriate tools were available (the Human Microbiome Project Consortium, 2012, Nature 486:207).
It is well documented that there is a general lack of diversity amongst cellular targets of approved antibiotics with recent reports estimating that fewer than twenty-five targets are represented (Fair and Tor, 2014, Perspect. Medicin. Chem. 6:25-64). Most of these compounds are non-discriminatory (broad-spectrum), and target essential pathways such as cell wall or protein synthesis (Walsh, 2000, Nature 406:775-781). Although some “narrow-spectrum” therapies are available, they target large subsets of bacteria (anaerobes vs. aerobes, Gram-positive vs. Gram-negative) instead of focusing on particular pathogenic species. The latter method of treatment would be preferred in an effort to reduce adverse side effects to the host and microbiome communities and to minimize the development of resistance; however, both financial and technical limitations have thwarted such efforts to date (Maxson and Mitchell, 2016, Tetrahedron 72:3609-3624). Furthermore, the identification of either 1) unique targets that would permit selective killing or 2) compounds that discriminate species is not trivial; this presents a clear unmet need that is ripe for discovery.
The combination of microbial diversity and evolutionary pressure has incentivized bacteria to create natural products with extraordinary selectivity and bioactivity. It should be noted that these scaffolds serve with distinction as antibacterial agents; an estimated 70% of marketed antibiotics are derived from natural products. One specific example exists within the rhizosphere where predominantly Gram-negative bacteria, particularly the Pseudomonads, utilize chemical warfare to both colonize the environment (quorum sensing) and defend themselves (antibiotics) (Keohane et al., 2015, Synlett 26:2739-2744; Philippot et al., 2013, Nat. Rev. Microbiol. 11:789-799). Of particular health interest is the bacterial species Pseudomonas aeruginosa (PA), an opportunistic environmental pathogen inherently resistant to many antibiotics yet rarely infective to healthy individuals (Gellatly and Hancock, 2013, Pathogens and Disease 67:159-173). However, those with compromised immune systems (i.e. burn victims, chemotherapy patients, and the chronically hospitalized) or cystic fibrosis are especially susceptible to a fatal infection. In 2013, the Centers for Disease Control listed Multi-drug resistant PA one of the top fifteen urgent/serious microbial threats facing society demonstrating a pressing need to develop new therapeutics which target this pathogen of interest (Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/threat-report-2013/(accessed Mar. 27, 2017)).
Recent efforts by both the De Mot (Vlassak et al., 1992, Plant Soil 145:51-63) and Muller (Hermann et al., 2017, Nat. Prod. Rep. 34:135-160) labs have focused on this call by targeting untapped resources within the soil, which are rich in diversity. Thorough work by both groups has revealed natural products with complex chemical architecture and unique bioactivity providing inspiration for organic chemists as platforms for further discovery. One such example is the Pseudomonad secondary metabolite promysalin, which is, as the name alludes to, derived from proline, myristate, and salicylate, which possesses species-specific inhibitory activity against PA, while inducing swarming and biofilm formation in a related species, P. putida (Li et al., 2011, Chem. Biol. 18:320-1330). In 2015, the first total synthesis of the natural product was completed, which elucidated the relative and absolute stereochemistry and also confirmed the reported biological activity (Steele et al., 2015, J. Am. Chem. Soc. 137, 7314-7317). It was also shown for the first time that promysalin repressed fluorescence of P. putida KT2440, which is presumably attributed to the inhibition of pyoverdine production by the bacterium.
Other Pseudomonad siderophores include pyochelin (Cox et al., 1981, proc. Natl. Acad. Sci. USA 78:4256; Schlegel et al., 2006, Natuforsch C. 61:263), pseudomonine (Anthoni et al., 1995, J. Nat. Prod. 58:1786; Sanely and Walsh, 2008, J. Am. Chem. Soc. 130:12282, Wuest, et al., 2009, J. Am. Chem. Soc. 131:5056), and ferrocin (Katayama et al., 1993, J. Antibiotics 46:65.
There is an interest in developing narrow-spectrum agents to combat Pseudomonas aeruginosa (PA) infections. PA is a Gram-negative pathogen that is typically found in people with weakened immune systems and/or hospital settings accounting for an estimated 51,000 infections/year in the United States alone (seudomonas aeruginosa in Healthcare Settings. (2014). Retrieved Mar. 19, 2016, from http://www.cdc.gov/hai/organisms/pseudomonas.html). The community has postulated that the rhizosphere, which is defined as the immediate area of soil that is directly influenced by microorganisms and root secretions, is an ideal environment to discover such compounds as the soil is teeming with Pseudomonads competing to establish their own (Keohane et al., 2015, Synlett 26:2739).
There is a need in the art for novel compounds with activity against PA infections. The present invention addresses this unmet need in the art.